Preparation of 2-methyl-1,4-naphthoquinone



Patented Oct. 12, 1943 UNITED STAT FICE l PREPARATION OF 2,-METHYL-L4- NAPHTHOQUINONE Robert W. Price, Orangeburg, and Gustaf H. Carlson, Pearl River, N. Y., assignors to Lederle Laboratories, Inc., New York, N-.

tion of Delaware Y., a corpora- No Drawing. Application January 31,1941,

Serial No. 376,868 I two recrystallizations *from methanol, "the, 2-

3 Claims.

naphthoquinone and Z-methyl-I l-naphthQqui-.

none-3-acetic acid. y

In general, the prior methods for preparing Z-methyl-1,4-naphthoquinone comprise the oxidation of beta-methylnaphthalene by means of chromic anhydride in a solution of acetic acid. One such method is described by Fieser (J. Biol. Chem. 133,392 (1940)) in which he states that the reaction is completed in about one hour as contrasted to the method described by Anderson (J. Biol. Chem. 103, 405 (1933)) which requires three days, or the method; described by Fieser in J. Biol. Chem. (J. A. C. S., 61, 3216 (1939)) which requires 36 hours and recovery of the product by steam distillation. The method described by Fieser involves adding chromic anhydride in a mixture of water and glacial acetic acid to a glacial acetic acid solution of beta-methyl-naphthalene while allowing the temperature to ris to about 60 C. after which the mixture is heated to about 90 C. for one hour and then diluted with a relatively large volume of water. The

crude precipitated productis then crystallized While the above prior art processes of adding the acetic acid solution of chromic acidto an When the product i to be acetic acid solution of beta-methylnaphthalene result in good average yields, they possess the disadvantage that in large scale production'consim erable quantities of oily or tarry products are produced which make th Z-methylnaphthoquinone difiicult to isolate andpurify, When relatively crude or impure chromic acid and betamethylnaphthalene are used in the processes,"

correspondingly larger quantities of oily or tarry substances are produced and the processes, therefore, usually require that the starting materials be relatively pure substances.

In prior methods for the preparation of 2- methylnaphthoquinone, the purification of the final product comprised recrystallization from methyl alcohol. We have found that, even after methylnaphthoquinone obtained is of anjinferior quality often containing as much as 0.01 to 0.02% of chromium. The. presence of such quantities of chromium makes the product undesirable as an anti-hemorrhagic compound itself-or as an intermediate in the preparation of vitamin K type-of naphthoquinones. L

In accordance with the present invention we have discovered that when the acetic acid S0111. tion of beta-methylnaphthalene is added to the acetic acid solution of chromic acid, instead of in the reverse order used in the prior processes; much smaller amounts of oily or tarry materials are produced and at the same time the yields are just as good andthe reaction is'completed in an equally short period of time. Further, the starting materials may be crude or impure without adverselyeffecting the reaction and the quality of 1 e 2,331,725 s PATENT 'OF Itis also an object of the present invention to provide aprocessfor the preparation oft2.-

methylnaphthoquinone which is easilycarriedout and which permits reproducibl yields of a product which is essentially free of chromium.

Broadly, our invention comprises the oxidation of 2-methyl-na'phthalene by means of chromic acid inthe presence of acetic acid to produce 2-methylnaphthoquinone under certainpreferred conditions to be hereafter described. The crude or impure Z-methylnaphthoquinone obtained bythe oxidation of Z-methylnaphthalene is dissolved in a water-immiscible organic solvent such as chloroform, which isQinert to or does not react with the Z-methyln'aphthoquinone. The solution is filtered to remove any solid material which may be present and is then washed with a dilute aqueous solution of aninorganic acid, such as 15-20% solution of hydrochloric acid,'which will form water soluble salts with chromium and which is inert toward the Z-methylnaphthoquinone The aqueous acid solution now containing also the chromium salti easily separated from the solution of the Z-methylnaphthoquinone in the organic solvent. This washing may be re- 1 peated oneor more times until all of the chro mic acid which contaminated the product has been removed. The solution of the product in the organic solvent is treated with a drying agent such as anhydrous sodium sulfat to remove water, after which a small amount of activated charcoal is added and the solution filtered. The solvent is then removed by distillation, preferably under vacuum; the solvent being recovered if desired, and the residue is crystallized from methanol. In a preferred method this residue is.

recrystallized from a mixture of methanol and The invention is further illustrated by the following specific examples, but the invention is not to be limited by the details set forth therein.

Example 1 glacial acetic acid In every. case the -bmght 5: l A solution of 1.42 kg. of technical Z-methylyellow crystalline proguct i? contams'not naphthalene in 1 liter of glacial acetic acid was more 3 "is; g glf m I h added during onehour, to a mechanically stirred In cmrymg out 6 a on 0 37 n p 7 solution of 5.87 kg. of chromio anhydride (99.5% thalene in accordance with ounimprovedprocess, granular grade) m 20 liters of glacial acetic the chromic acid is dissolved in 80% acetic acid acid and; liters of water maintained at and the zmethylnaphthalene dissolvedin i peraturesbetween 30-65" 0. As soon as the sponf f g 35 to g iggg i zfig taneous reaction was completed the mixture was y S an C00 6 so Ion heated to Gil-65 C. for fifteen minutes, and added The addition of the glacial acetic acid 50111111013. to liters of cold Water, stirred vigorously g u if gii gg (5-10. minutes). The precipitate was collected a ma f g z 2 9 b t in a. centrifuge and washed with 10-15 liters of 333 8 5 2 a g n 1' cold water (until the filtrate was colorless). The reaction miyturi is hzated to zbofit fi l i li to? mqist fprecipitg'te g dissolved Ef v ch oro orm, t e so ution was trea ed wi egigi zggi g gf gi gt iz gg fi colorizing charcoal g.)., filtered, washed with V I v f i 1 liter of 18% hydrochloric acid, with 1 liter of g gf figig l fgg gf i ii if; water, dried with sodium sulphate (50-100 g.) centrifuge preferably, and washed with several gi g gg g i g 3 3 33: was dlstmed from the v i r o e 58 23:; igi mg g gf gz g gig g z iigz The residdue. was dissolved in 0.3 liter of glacial a ct uch 1 ready for the purification" treatment as outlined 5 5 -152 2 gg i g i ggfii i gigq fl q r This improved pmcess has Several talline product which formed (yield 1275-1328 a solution of the hydrocarbon dissolved in glacial 5 3 351; fi z g gfig g f gg gg 5&2; acetic acid to the 'chromic acid solution permits in forty Simiiar preparatm contained M the use of smaller quantities of glacial acetic tectable quantity ofchmmium acid than was possible by theprior'art processes. The yield Of crystalline quino'ne after the first 3153 531 33 25233 25333256i gziig fig fig crystallization, is 34% and the mother liquor,

" ft drocarbon solution be added to the larger volume f ggiii i f izi ggg gi yigl 313 of'chromi'c acid solution rather than in reverse miumqreg 'crystamzed qumona amounts of order using larger volumes of weaker hydrocar- 12754328 or a yield of r Yields of gg g g gg r: n g r igr5::- pgggl mg gfi zg this order of magnitude are regularly obtained by y L r smaller amounts of oily or tarry products, and e p ocess Example 2 hence the final product is much easier to isolate. Thehoxmauon is complete in a relatively Short The same general procedure described in Ex- .mne; the, conditions are such that reproducible ample 1 was employed with certain variations in results are easily obtained; and the process does 9 F 2"? ffi fi g results are not require the use of pure starting materials. manze m e 0 Owing ta TABLE I Tcm- Tem- Wt 'r r 'r r 5 Batch 3 E8 t aleig g g g zeurrz- M. P. Yield Cr analysis I Hrs. Min. 0. Hrs. Min. C. Grams C. Percent XVILL. 3' l5 1 15 ('0) 900 102-6 26 Purified same as Ex- XVHB 13 (b) ample l and there time: first? XVIII-1%: a 30 15 1,100 102-5 32 umwoolw mess 1, 050 104-5 31.4 xrxra--- a 20 211 1 14 XXA a 20: 22s 1 14 1,080 104-0 31.4 XXB... it 28 XXHL. 2 15 25-30 1 55 1,080 102-5 31.4

xxrv.. 1 15 40-45 1 40 1,085 102-5 31.6

xxv 1 45-50 1 952 101-5 28 XXVI--. 1 45-50 1 50 1, 030 102-0 30 xxvn 51 45-50 1 50 1, 075 1026 31 I With external ice cooling. At room-temperature.

= The chloroform solutions of the crude product were combined and solvent was removed in vacuo.

The

rvsidoe was crystallized from a hot solution in 600 cc. of acetic acid and five liters of methanol.

Slowly brought to 3d and precipitated immediately.

peratureremained about 60 C. The addition requiredjl hour and 40 minutes, and after remaining at 40 C. for hour the reaction mixture was heated to 80-90 C. for 40 minutes. The quinonewas precipitated as usual in 50 liters of water, filtered ofi, Washed with liters of water and dried as much as possible on the filter. The product was crystallized from editors of hot methanol and 455 g. (26.5% yield) of greenish ycn w crystals (M. P. 100- 105 C., Cr=1.425%) were obtained. Evaporation of the mother liquor yielded 110 g. of dark colored, gummy-material (total: 565 g., 33% yield). r

The first crop of crystals (455 g.) were divided in halfand portion (1) purified according to the method of this invention, portion (2) purified according to prior methods.

Portion (1) ;-(227.5 g.) was dissolved in chloroform, thesoluti'on decolorized with charcoal and extracted with 18%; (aqueous) hydrochloric acid.

The quinone residue, obtained by removal of the solvent from the dried solution, was dissolved in 80 cc. glacial acetic acid, 1 00 cc. ofhot methanol added and the product allowed to crystallize.

155 g. (M. P."-104-'106'C., (EL-0.0022,)v of bright yellow needles were obtained. Concentration of the mother liquor caused 29 g. (M. P. 92-100 C.) of

bright'yellow-solidto separate, and complete re moval of the solventleft 31 g; of black oily solid. Portion (2), (227.5 g.) wasidissolved in- Bliters of hot methanol and 4.5 g. dark brown insoluble material filtered off. Concentration of the filtrateto 1200'cc. caused 158 g. of brown coldred quinone (M, P. 101-l05.5 0., Cr=0.0825%) to crystallize.

Further concentration of. the" mother liquor yielded ll'g. (M. P, 92-101 C.) of brown solid, and

evaporation'of the solvent from the remaining solution left'17 :g. of a brown solid residue.

It is apparent that themethod usedito purify portion (1) gave a more satisfactory product with regard to colon-meltingpoint, and low chromium content. In order toyfurther; substantiate this observation, the first crop of crystals obtained from portion (2) (158g) was treated as portion (1 .121 g'iof quinone. (M. P. 105-106" C., Cr,=0.001%) were obtained, in the first crop of crytsals, 29g. upon concentration of the mother liquor, and 31 g. of black oily solid upon evaporationto dryness. By this single treatmentthe melting pointwas brought. up to the recorded, value, and the chromium content decreasedeighty fold.a; 1

i l'Eatam'ple 4 Further experiments were oarried out to deter-. minethe yield and nature ,of the products obtained when the order of mixing described .by the'prior art was followed. Ifhe results are tabulated in the following table: r

TABLE II Wt. CrOs AcOH Wt. Me- Time of Or. in plus H2O naphthalenein ACOH addition 3332;: M'P Ylem analysis Per ccnt gPerce'nt l 50 g. V cc." Y j 35 cc. 14.2 g. 150 cc. Y 39.5 1 0.018 g. 35cc. 3500. 14.2 g. 150cc. 20.0 0.010 e g 1 (technical) e 345g. 245 c. 245cc. g. 1,000 cc; 29 0.0155

4 345 g. 245cc. 245cc. 100 g. 1,060 cc. as 0597 I 100 g. r 27 V 345 g 245 cc. I a 245cc. (technical) 1,050 135 34 I 0.415

345 a 245 cc. 245cc. (technical) 1,000 a. 345g. I 245 cc'. 245cc. 100g. I 1,0 0 cc. 0.334 T301 0.101s 5kg. 3.51. 3.51. .42k 151.- V ,24 M11 I 5 10 0.008 5k 3.51. 3.51. 1.42kg. 151... 23 11.0.

' V I 1 42]: I g. Y 10--.. 5kg. 3.51. 3.51. (technical) 151. 20.5 0.0825

11---- 400 g. N 1,500 cc. 552 cc. (technical) 141cc. 33 0.0003 12..-- 200g. 750 cc. 181 cc. (technipal) 70.5 cc. 11.5. nkl- First crop. b Residue. v

6 Second crop.

. d Crude quinone dissolved in 2.3 liters of chloroform, water was removed and solvent distilled. The residue was crystallized from 2 liters of methanol and yielded a brown product. Obtained by recrystallization of from 2 liters of methanol. 1

v 1 Crude, dry qninone dissolved in chloroform, washed with 18% E01, dried with sodium sulfate, decolorized with charcoal, solvent distilled in vacuo, residue dissolved in'acetic acid, methanol added and the quinone crystallized.

5 Third crop.

11 Product obtained from methanol solution.

i Evaporation of mother liquor left g. of dark, gummy material. Vi Obtained from one half (227.5 g.) of the prior art method purified quinone carried'through our chloroform process.

Concentration of the solution yielded 20 g. (M. 1?. 92-100") yellow solid and complete cvaporationofthe solvent left 31 g.

black oily solid k Obtained from the other half of the prior art method purified quinone by dissolving in hot methanol, filtering, c0ncentrating and allowing to cool. The product was brown colored. Concentration of the mother liquor yielded 41 g.

(M. P. 92-101") brown s'olidand removal of the solvent left 17 g. brown solid.

1 Obtained by treating (1:)(150 g.) by chloroform process. r Ethylene dichloride solution of crude quinone washed with 20% ECl.

, ,Chloroform solution of one half of the crude quinone washed with 25% sulphuric acid. I

v Ethylene dichloride solution 01 one half of the crude quinone washed with 25% sulphuric acid.

Isolated from mother liquor.

An examination of thedatain the Table .II re "an that inrExperiments 1 and 2 the respective yields of purified quinone were 39.5' and 29.5%. In Experiment 1 a high grade of 2-methylnaphthalene'was used; whereas in Experiment 2 crude zmiethylnaphthalene was used; and the low yield in Experiment 2 is attributed to the use of the poor grade of hydrocarbon. Increasing the amount of hydrocarbon to 100 grams in Experiments 3 and 4 did not alter the yield of the quinone. However, with an increase in hydrocarbon to 1.4 kg. in Experiments 8, 9, and the I yield dropped to 26-28%. In Experiments 3, 4,

5, 6, and '7 evaporation of the solvents from which the quinone had been crystallized left a dark tarry residue from whichno quinone could be isolatcd. Apparently, therefore, under the conditions of these oxidation processes, products other than the quinone are-produced.

' Purification of the crude" oxidation product according to the method described in the priorart gave aquinone containing from 0.0156 to 1.825% chromium as determined spectrophotometrically. in Experiment 10. the-crystallized product was purified by the improved process of the present invention by dissolving in chloroform, treating with charcoal, filtering, and washing with hydrochloric acid. The chloroform was then removed by vacuum distillation and the residue crystallized from a mixture of 80 cc; of glacial acetic acid and 1100 cc. of the methanol. An analysis then showed a chromium content of only about 0.002%. Itis seen, therefore, that this procedure clearly diminished the chromium value to about /900; whereas mere crystallization of the product of Experiment 10 (chromium 1.835%) from hot methanol decreased the chromium value only to 0.0825 Purification of this product through solution in chloroform, treatment with hydrochloric acid, and charcoal as previously described, decreased the chromium value to 0.001% and this experiment serves to show that the latter method of purification is mor effective for reducing the chromium content than mere crystallization from methanol. Further proof of a slow removal of chromium by mere recrystallization from methanol is obtained. from Experiment 8, in which the value decreased only from 0.018 t 0.011%, notwithstanding that the original product had been largely separated from the impurities by extraction with chloroform and crystallization from methanol. In experiment 9, the crude product was extractedwith chloroform, the solution was treated with 18% hydrochloric acid and decolorizing charcoal and the product,

after crystallization from methanol, contained fication showed a chromium content of only 0.0003% in Experiment 11 and was not detectable in Experiment 12, in which sulphuric. acid was substituted for hydrochloric. acid during purification. One-half the product of Experiment 12 was extracted with chloroform and the other half was extracted with ethylene dichloride and this solution was treated with sulphuric acid and decolorizing charcoal accordin to the abovementioned process. The product so purified again showed no detectable amount of chromium. Accordingly, this experiment shows that sulphuric acid may be substituted for hydrochloric acid in the purification process.

This experimental work shows that preparation of 2-methyl-naphthoquinone according to the method described in the prior art yields a product containing considerable amounts of chromium and that oily or tarry products are sometimes formed. Whereas the productsin small batches are relatively easily purified, those from larse-scale operations cannot be adequately purified by mere crystallization without undue loss of material. Invariably the crude product was highly colored and even after recrystallizations the products remained somewhat discolored.

In the methods for purification of the 2- methylnaphthoquinone described in the examples, chloroform was used as the water-immiscible solvent and dilute hydrochloric acid was used for removing the chromium. The chloroform may be replaced by other suitable waterimmiscible organic solvents, such as for example, other chlorinated hydrocarbons, ethers, carbocyclic hydrocarbons such as toluene, benzene, chlorotoluene, benzochloride, xylene, and the like. Similarly the dilute hydrochloric acid may be replaced by other acids, for example, sulfuric acid, and the like.

What we claim is:

1. An improved method for the preparation of 2-methyl-1,4-naphthoquinone which comprises adding a solution of Z-methylnaphthalene in glacial acetic acid to a solution of chromic acid in approximately 80% glacial acetic acid while maintaining the temperature of the reaction mixture within the range of about 30 to 65 and diluting with a relatively large volume of cold Water to precipitate the 2-methyl-1A-naphthoqumone,

2. An improved method for the preparation of 2-methyl-1,4-naphthoquinone which comprises adding a solution of 2-methyl-naphthalene in only 0.0089% of chromium. From the mother '1 liquor in Experiment 9 a second crop of quinone was isolated containing no detectable quantity of chromium, and even the third crop of crystals contained only 0.001% chromium. In part the high chromium content; obtained in Experiments (4-10) is attributable to the use of chromium oxtrio of a. purity of only 99.5%, but the analytical data of Experiments 1-3 show that even with the reagent grade of oxide, the chromium content of the quinone as prepared by the prior art; method is considerably higher than permissible in products intended for pharmaceutical uses.

As further evidence of the efiicacy of the purification by chloroform extraction and treatment with acid, the results of Experiments 11 and 12 are cited. With the small quantity of methylnaphthalene used in these experiments (100 g. and 50 g. respectively), the product after puriglacial acetic acid to a solution of chromic acid in approximately glacial acetic acid while maintaining the temperature of the reaction mixture within the range of about 30 to 65 C., after the addition is complete maintaining the mixture at a temperature of about 65 C. for a short time, diluting with a relatively large volume of cold water to precipitate 2-methyl-1,4-naphthoquinone, removing the precipitate, dissolving it in chloroform, washing said chloroform solution at least once with a dilute aqueous solution of hydrochloric acid, separating the chloroform solution from the dilute acid solution, recovering the 2- methyl-1,4-naphthoquinone from the chloroform by evaporation of the latter, dissolving the residue in and recrystallizing from a mixture of methanol and acetic acid.

3. An improved method for the preparation of 2-methyl-1,4-naphthoquinone which comprises adding a solution of Z-methyl-naphthalene in in glacial acetic acid to a solution of chromic acid in approximately 80% glacial acetic acid while tion at least once with a dilute aqueous solution of maintaining the temperature of the reaction an inorganic acid, separating the chloroform mixture within the range of about 30 to 65 0., solution from the dilute acid solution, recovering after the addition is complete maintaining the the 2 methyl 1,4 -naphthoquinone from the mixture at a temperature of about 65 C. for a chloroform by evaporation of the latter, dissolvshort time, diluting with a relatively large volume ing the residue in and recrystallizing from a mixof cold water to precipitate 2methy1-1,4-naphture of methanol and acetic acid.

thoquinone, removing the precipitate, dissolving I ROBERT W. PRICE.

it in chloroform, washing said chloroform solur Y GUSTAF H. CARLSON. 

